Anumberofdrugsknownasanticholinesterases interferewithacetylcholinesteraseandtherebyenhancetheactionofacetylcholinebyprolongingitspresenceatitssynapses.Suchdrugsincludeinsecticidesandchemicalwarfareagents,aswellassometherapeuticdrugs,suchasthoseusedtotreatmyasthenia gravis. Myastheniagravisisanautoimmunediseaseinwhichantibodiesbindtoacetylcholinereceptorsattheneuromuscularjunction,therebydisruptingtheirfunctionalityandcausingthemtobemorerapidlydegraded.Thisreductioninreceptorsleadstosevereweaknessandultimatelyparalysis.Theweaknessischaracterizedbyrapidtiringofthemusclewithrepeateduse.Rapidtiringoccursbecausethenumberofpresynapticvesiclesavailableforreleasedropsduringthehigh-frequencytrainofmotorneuronactionpotentialsthatgeneratessuchcontractions.Normally,becauseofthehighsafetyfactoroftheneuromuscularjunction,smallerbutstillsuprathresholdEPPswouldstillbegeneratedandmaintainmusclecontractionduringrepeateduse.Inpeoplewithmyastheniagravis,thesafetyfactorissoreducedbythelossofacetylcholinereceptorsthatthedecreaseinreleaseofacetylcholinewithrepeatedactivityleadstoEPPsthatfailtotriggerspikes,andthusmuscularcontractionfails.Standardtreatmentsincludeanticholinesterases,whichallowagreaterconcentrationofacetylcholinetopartiallyovercomethedeficitcausedbythereducednumberoffunctionalpostsynapticreceptors,andimmunosuppressivetherapiesandplasmaexchange,whichreducelevelsofautoantibodiesagainsttheacetylcholinereceptor.Thesetherapiesareallrelativelynonspecificandcanthereforehavemanysideeffects.PotentialfuturetherapiesarebeingdevelopedandincludeinducingtolerancetotheacetylcholinereceptorandselectivedestructionoftheBcellsthatmakeantibodiesagainstthereceptor.
Acetylcholine is synthesized from acetyl coenzyme A and choline by the enzyme choline acetyltransferase, which is located in the cytoplasm of cholinergic presynaptic terminals. After synthesis, acetylcholine is concentrated in vesicles. After release, the action of acetylcholine is terminated by the enzyme acetylcholinesterase, which is highly concentrated in the synaptic cleft. Acetylcholinesterase hydrolyzes acetylcholine into acetate and choline. The choline is then taken up by an Na+ symporter in the presynaptic membrane for the resynthesis of acetylcholine. The extracellular enzymatic degradation of acetylcholine is unusual for a neurotransmitter inasmuch as the synaptic action of other classic neurotransmitters is terminated via reuptake by a series of specialized transporter proteins.
•Fig. 6.11 Glutamatetransportcycle.A, Schematicshowsthefateofglutamatereleasedfromapresynapticterminal.Distinctglutamatetransportersexistonthepresynapticandpostsynapticcellmembranesforreuptake.Inaddition,glialcellstakeupglutamateandconvertittoglutamine.Theglutamineisthenreleasedandtakenintothepresynapticterminal,whereitisconvertedbacktoglutamatebeforebeingrepackagedintosynapticvesicles.B, Schematicoftransportershowingdirectionofionflowassociatedwiththemovementofglutamateacrossthemembrane.
A variety of amino acids function as neurotransmitters. The three most important are glutamate, glycine, and GABA.